The second European interdisciplinary Ewing sarcoma research summit - A joint effort to deconstructing the multiple layers of a complex disease

Abstract

Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second “European interdisciplinary Ewing sarcoma research summit” assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.

Efficient Recreation of t(11;22) EWSR1-FLI1+ in Human Stem Cells Using CRISPR/Cas9

“…In line with previous studies (Kovar et al., 2016), despite being possible to induce the t(11;22) in hMSCs over the short term, the fusion gene was not compatible with hMSC viability/homeostasis and the t(11;22)-edited hMSCs were progressively lost in culture (data not shown). Because Ewing sarcoma is composed by poorly differentiated cells of unknown origin (Kovar et al., 2016), we next sought to generate the t(11;22) translocation in human iPSCs.…”

“…This finding is in agreement with recent studies of Ewing sarcoma suggesting that MSCs might not represent the target cell-for-transformation in Ewing sarcoma (Kovar et al., 2016, Minas et al., 2016, Renouf et al., 2014, Rodriguez et al., 2011). We therefore attempted to induce the t(11;22) translocation in a less differentiated cell type.…”

“…Because Ewing sarcoma is composed by poorly differentiated cells of unknown origin (Kovar et al., 2016), we next sought to generate the t(11;22) translocation in human iPSCs. These difficult-to-target cells are an invaluable biological tool for disease modeling and biomedical research (Sancho-Martinez et al., 2016).…”

EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

“…With the advent of sensitive single‐cell gene expression analysis methods, it is becoming increasingly clear that stochastic variation in oncogene expression levels exist between individual cells of a tumor. This was recently demonstrated for FUS‐DDIT3 positive myxoid liposarcoma and discussed for EF in ES at the 2nd European Ewing Sarcoma Research Summit . Here, such stochastic variations in EF expression may translate into differential metastatic behavior, since EF‐low cells were demonstrated to have drastically increased migratory and metastatic potential .…”

Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

“…It is also associated with systemic inflammation, including elevated white blood cell counts and C-reactive protein levels, each of which is correlated with poor prognosis 17 . Survival of patients with metastatic disease is poor and has not significantly improved over the past 20 years 18,19 , in spite of high dose therapy and allogeneic stem cell transplantation 20 . Here we describe a role of EwS EVs in transmitting retroelement and pericentromeric RNAs into stromal fibroblasts and immune cells, and in expansion of immunosuppressive CD33 + HLA-DR -, CD33 + CD25 + , CD33 + PD-1 + MDSC-like and CD8 + CD25 + PD-1 + Tcells in peripheral blood of EwS patients.…”